Current treatments for Parkinson's disease (PD) become increasingly less efficacious as the disease progresses, and do little to slow the underlying pathophysiological changes in the nigrostriatal dopaminergic system (Rascol, O., et al., Limitations of Current Parkinson's Disease Therapy, Ann. Neurol., 53 Suppl 3:S3-12 (2003); Romell, J., et al., Rationale for Current Therapies in Parkinson's Disease, Expert Opin. Pharmacother., 4:1747-1761 (2003)). Neurotrophic factors, proteins which activate cell signaling pathways regulating neuronal survival, differentiation, growth and regeneration, offer promising therapy for treating dopamine neurons in PD, but are difficult to administer clinically as they do not pass through the blood brain barrier (Beck, K. D., et al., Mesencephalic Dopaminergic Neurons Protected by GDNF from Axotomy-Induced Degeneration in the Adult Brain, Nature, 373:339-3416 (1995); Bjorklund, A., et al., Towards a Neuroprotective Gene Therapy for Parkinson's Disease: Use Of Adenovirus, AAV and Lentivirus Vectors for Gene Transfer of GDNF to the Nigrostriatal System in the Rat Parkinson Model, Brain Res., 886:82-98 (2000)). Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor shown to dramatically protect and enhance the function of dopamine neurons in vitro and in vivo in rodents and monkeys (Beck, K. D., et al., (1995); Bjorklund, A., et al., (2000); Gash, D. M., et al., Functional Recovery in Parkinsonian Monkeys Treated with GDNF, Nature, 380:252-255 (1996); Grondin, R., et al., Striatal GDNF Infusion Promotes Structural and Functional Recovery in Advanced Parkinsonian Monkeys. Brain, 125:2191-2201 (2002); Grondin, R., et al., GDNF Increases Stimulus-evoked Dopamine Release and Motor Speed in Aged Rhesus Monkeys, J. Neurosci., 23:1974-1980 (2003); Hebert M. A., et al., Functional Effects of GDNF in Normal Rat Striatum: Presynaptic Studies Using In Vivo Electrochemistry and Microdialysis. J. Pharm. Exp. Ther., 279:1181-1190 (1996); Hebert M. A. and Gerhardt, G. A., Behavioral and Neurochemical Effects of Intranigral GDNF Administration on Aged Fischer 344 Rats. J. Pharm. Exp. Ther., 282:760-768 (1997); Hou, J. G. G., et al., Glial Cell line-Derived Neurotrophic Factor Exerts Neurotrophic Effects on Dopaminergic Neurons In Vitro and Promotes Their Survival And Regrowth After Damage by 1-Methyl-4-Phenylpyridinium. J. Neurochem., 66:74-82 (1996); Kordower, J. H., et al., Clinicopathological Findings Following Intraventricular Glial-Derived Neurotrophic Factor Treatment in a Patient with Parkinson's Disease. Ann Neurol., 46(3):419-424 (1999); Kordower, J. H., et al., Neurodegeneration Prevented by Lentiviral Vector Delivery of GDNF in Primate Models of Parkinson's Disease. Science, 290:767-773 (2000); Palfi, S., et al., Lentivirally Delivered Glial Cell Line-derived Neurotrophic Factor Increases the Number of Striatal Dopaminergic Neurons in Primate Models of Nigrostriatal Degeneration. J. Neurosci., 22:4942-4954 (2002); Tomac, A., et al., Protection and Repair of the Nigrostriatal Dopaminergic System by GDNF In Vivo, Nature, 373:335-339 (1995)). However, initial clinical trials involving ventricular delivery of GDNF showed no statistically significant differentiation of the placebo and active treatment groups (Nutt, J. G., et al., ICV GDNF Study Group. Implanted intracerebroventricular. Glial Cell Line-derived Neurotrophic Factor. Randomized, Double-Blind Trial of Glial Cell Line-Derived Neurotrophic Factor (GDNF) in PD, Neurology, 60:69-73 (2003)), perhaps because insufficient amounts of GDNF reached critical target sites from the CSF (Ai, Y., et al., Intraputamenal Infusion in Aging Rhesus Monkeys: Distribution and Dopaminergic Effects. J. Comp Neurol. 461: 250-26125 (2003); Kordower, J. H., et al., (2000)).
Consequently, there continues to exist a long-felt need for effective methods for the treatment and prevention of PD in humans. Accordingly, it is an object of the present invention to provide methods of treating PD in humans comprising intraputaminal convection-enhanced infusion of GDNF. This and other such objectives will be readily apparent to the skilled artisan from this disclosure.